Currently, there is a need for novel, potent, and selective agents to prevent and or treat cancer, particularly melanoma, cancer of the cervix, or leukemia. One of the methods currently under study is selective induction of apoptosis. There is also a need for pharmacological tools for the further study of the physiological processes associated with selective induction of apoptosis.
Programmed cell-death (apoptosis) is critical for tissue homeostatis, for the physiological removal of unwanted cells during development and in host defence mechanism (Vaux et al., Cell, 96:245 (1999)). Inhibition of apoptosis is implied in every known human malignancy. This inhibition provides malignant cells with a selective growth advantage, allowing survival in the face of radiation or chemotherapy. (See Reed, Curr Opin. Oncol., 7:541 (1995), and Kelekar et al., Trends Cell. Biol., 8:324 (1998).) The Bcl-2 family of proteins are believed to be important regulators of apoptosis; pro-survival members of this family, such as Bcl-xL, contain, on the surface, an hydrophobic groove in which is believed to allow binding of the BH3 domain of the pro-apoptotic counterpart (Johnstone et al., Cell, 108:153 (2002)). This binding is believed to be crucial for apoptosis regulation, in fact pro and anti-survival proteins can reverse each other function through dimerization. It is believed that the anti-apoptotic Bcl-2 family members are generally overexpressed in many human malignancies. These observations have lead to a growing interest in the discovery of small molecules, targeting anti-apoptotic proteins of the Bcl-2 family, and mainly, Bcl-xL, as potential anticancer therapeutic agents (Wang et al., Proc. Natl. Acad. Sci. U.S.A., 97:7124 (2000)), Degterev et al., Nat. Cell Biol., 3:173 (2001); Tzung et al., Nat. Cell Biol., 3:183 (2001); Enyedy et al., J. Med. Chem., 44:4313 (2001)). However, until now the proposed compounds failed to fully corroborate the role of Bcl-xL inhibitors as potential anti-cancer agents (Kaneko et al., Bioorg. Med. Chem. Lett., 11:887 (2001); Chin et al., Angew. Chem. Int. Ed. Engl., 40:3806 (2001); Kutzki et al., J. Am. Chem. Soc., 124:11838 (2002)) because of either their poor in vivo activity or the in vitro low affinity.
Therefore, a need exists to identify potent cell permeable compounds for targeting the Bcl-2 family of receptors such as, for example, Bcl-xL, Bcl-2, Mcl-1, or Bcl-B. There exists a need for agonists that can inhibit the binding of BH3 to the Bcl-2 receptors.
In addition a need exists for compounds useful as chemosensitizers in particular for cancer types where anti-apoptotic Bcl-2 family proteins, such as Bcl-xL, Bcl-2, Mcl-1, Bcl-W, or Bcl-B, are over produced by the cancer cells (such as, for example, lymphomas, neuroblastoma, breast cancer, lung cancer, prostate cancer, ovarian cancer, leukemias, and the like).